Human endogenous retroviruses (HERVs) result from the integration of retroviral DMA into germ cells. The HERV-K(HML-2) proviruses represent the most recently integrated HERV group. Although most are defective, HML-2 proviruses with intact open reading frames in some or all genes exist. HML-2 have been under purifying selection, suggesting reinfection, and their insertion rate appears constant during hominid evolution. HML-2 expression has been associated with brain disorders, particularly schizophrenia, by the presence of viral particles, genomic RNA, or transcripts. The consequences of HERV expression in human brain tissue are poorly understood. We hypothesize the existence of an replication competent HML-2 provirus whose expression has negative genetic effects on nearby cells. Although infectious viruses could potentially be generated from multiple loci in trans, an intact provirus could alone produce infectious virus, the most likely candidates for which are very recent insertions. We propose to identify novel HML-2 polymorphic insertions in humans using a combination of blotting, PCR, cloning, and sequencing. The incidence of each newly identified HML-2 provirus and disease will be analyzed in a high-throughput PCR screening of human DNA samples. Finally, we will look for HML-2 insertions in DNA extracted from schizophrenia-associated brain tissue against age-matched controls using blotting and PCR techniques. New, clonal HML-2 insertions detected in such an analysis would provide strong evidence of an expressed, replication competent HML-2 provirus. Close proximity of a new integration to a host coding region will be considered as preliminary evidence for a model of transcriptional alteration, and would provide the basis for further studies. An inherited HML-2 provirus with a significant incidence in patients with schizophrenia would be an important discovery. This knowledge would affect not only the diagnosis of the disease, but strategies for prevention and treatment could be adjusted appropriately as an alternative to current methods. Schizophrenia currently affects about one percent of the United States population and costs the public nearly $100 billion each year (National Institutes of Mental Health). Recently integrated proviruses may be genetically linked to this mental disorder through the expression of inherited endogenous loci, the most likely of which belong to the HERV-K(HML-2) group of retroviruses. The goal of this proposal is to clarify the relationship between HML-2 expression and schizophrenia by either establishing a genetic linkage of an inherited provirus with the disorder, or demonstrating the presence of novel proviruses in brain tissue from the patients diagnosed with schizophrenia versus age-matched controls.